Project 1 - Ascending thoracic aortic aneurysms progressively enlarge over time, typically leading to an[unreadable] acute type A dissection in the absence of prophylactic surgical repair. Therefore, thoracic aortic[unreadable] aneurysms and type A dissections are associated conditions and are termed TAAD for this proposal. We[unreadable] determined that TAAD is inherited in an autosomal dominant manner with variable expression and[unreadable] decreased penetrance in up to 15% of TAAD patients. We mapped the first three loci for the condition[unreadable] and have determined that the defective gene at the TAAD2 locus is transforming growth factor beta receptor[unreadable] type II (TGFBR2). Identification of TGFBR2 as the defective gene at the TAAD2 locus has provided[unreadable] insight into the role of TGF-beta signaling as a mechanism leading to aneurysm formation. Our preliminary[unreadable] data demonstrates the surprising finding that although the TGFBR2 R460 mutations disrupt TGF-beta[unreadable] signaling when expressed in cells lacking the wild type receptor, aortic smooth muscle cells (SMCs)[unreadable] explanted from patients heterozygous for the mutation demonstrate paradoxical upregulation of TGF-beta[unreadable] signaling in the absence of stimulation with TGF-beta ligand. Furthermore, the majority of aortic SMCs[unreadable] explanted from unrelated patients with familial TAAD who do not have TGFBR2 mutations (5 out of 6 cell[unreadable] strains) demonstrate the same paradoxical upregulation of TGF-beta signaling in the absence of ligand.[unreadable] Based on our genetic studies and preliminary data, we hypothesize that dysregulation of TGF-beta signaling[unreadable] in aortic SMCs is common in familial thoracic aortic aneurysms and dissections. The first aim is to[unreadable] determine the mechanism leading to stimulation of the TGF-beta pathway in the absence of ligand in[unreadable] aortic SMCs heterozygous for the TGFBR2 mutation. We will then proceed to characterize the[unreadable] phenotype of these aortic SMCs. In addition, we will determine the frequency of dysregulation of TGF-beta[unreadable] signaling in aortic SMCs explanted from familial and sporadic TAAD patients and investigate the etiology[unreadable] of this dysregulation. Finally, we will characterize the clinical phenotype associated with TGFBR2[unreadable] mutations using four mutigenerational families. The long-term goal of these studies is to identify the[unreadable] genes that predispose individuals to familial TAAD and determine the phenotype associated with these[unreadable] mutations so that proper clinical management can be provided to prevent premature deaths in these[unreadable] families. In addition, we hope to develop rational therapy to treat this fatal disease through the[unreadable] characterization of molecular pathways leading to this disease.